Inhibitory effects of class I and IV antiarrhythmic drugs on the Na+-activated K+ channel current in guinea pig ventricular cells

Abstract

Recently we have reported that class III antiarrhythmic drugs including amiodarone inhibit the Na⁺-activated K⁺ (K_Na) channels in isolated cardiac cells. In this study effects of antiarrhythmic drugs having class I and/or IV properties on the single K_Na channel current were examined in inside-out membrane patches of guinea pig ventricular cells by using patch clamp techniques. The K_Na channel current, which was activated by increasing [Na⁺]_i from 0 mM to 100 mM in the presence of 150 mM [K⁺]_o, showed a large slope conductance (212 pS) and inward-going rectification. Quinidine (100 µM), mexiletine (100 µM) and flecainide (10 µM) were selected as representative of class Ia, Ib and Ic drugs, respectively. These drugs at relatively high concentrations incompletely inhibited the K_Na channel by decreasing the open time (flickering block). The class IV drug verapamil inhibited the K_Na channel current mainly by decreasing the open probability although the IC₅₀ value of verapamil (3.36 µM) was higher than the therapeutic concentrations. Bepridil and SD-3212, antiarrhythmic drugs having both class I and IV properties, potently inhibited the K_Na channel current by decreasing the open probability. The IC₅₀ values of bepridil and SD-3212 for inhibiting the K_Na channel current was 0.51 µM and 0.53 µM, respectively, both of which are within the therapeutic range. Most antiarrhythmic drugs inhibit cardiac K_Na channels by different modes and at different concentrations. The K_Na channel blocking action of bepridil and SD-3212 may partly contribute to the prolongation of the action potential duration by these drugs at rapid stimulation rates.